Single-chain heteropolymers transport protons selectively and rapidly

Jiang, Tao; Hall, Aaron; Eres, Marco; Hemmatian, Zahra; Qiao, Botao; Zhou, Yanzhao; Ruan, Zhiwei; Couse, Andrew D.; Heller, William T.; Huang, Haiyan; Cruz, Mónica Olvera de la; Rolandi, Marco; Xu, Ting

doi:10.1038/s41586-019-1881-0

Cited by 81 publications

(94 citation statements)

References 48 publications

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“…All the covalent bonds were constrained, which supported an integration time step of 2.5 fs. These parameters were recommended for the accurate reproduction of the original CHARMM simulation on lipid membrane system 38 and were verified in simulations on proteins 20,39,40 and lipid membranes 41 . The production simulation lasted 100 ns.…”

Section: Figure 4 Simulation Methods In the Absence (B-e) And Presencmentioning

confidence: 95%

The Distal Polybasic Cleavage Sites of SARS-CoV-2 Spike Protein Enhance Spike Protein-ACE2 Binding

Qiao

Cruz

2020

Preprint

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The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein plays a crucial role in binding the human cell receptor ACE2 that is required for viral entry. Many studies have been conducted to target the structures of RBD-ACE2 binding and to design RBD-targeting vaccines and drugs. Nevertheless, mutations distal from the SARS-CoV-2 RBD also impact its transmissibility and antibody can target non-RBD regions, suggesting the incomplete role of the RBD region in the spike protein-ACE2 binding. Here, in order to elucidate distant binding mechanisms, we analyze complexes of ACE2 with the wild type spike protein and with key mutants via large-scale all-atom explicit solvent molecular dynamics simulations. We find that though distributed approximately 10 nm away from the RBD, the SARS-CoV-2 polybasic cleavage sites enhance, via electrostatic interactions and hydration, the RBD-ACE2 binding affinity. A negatively charged tetrapeptide (GluGluLeuGlu) is then designed to neutralize the positively charged arginine on the polybasic cleavage sites. We find that the tetrapeptide GluGluLeuGlu binds to one of the three polybasic cleavage sites of the SARS-CoV-2 spike protein lessening by 34% the RBD-ACE2 binding strength. This significant binding energy reduction demonstrates the feasibility to neutralize RBD-ACE2 binding by targeting this specific polybasic cleavage site. Our work enhances understanding of the binding mechanism of SARS-CoV-2 to ACE2, which may aid the design of therapeutics for COVID-19 infection. TOC:The SARS-CoV-2 spike protein-ACE2 complex showing the polybasic cleavage sites

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Section: Figure 4 Simulation Methods In the Absence (B-e) And Presencmentioning

confidence: 95%

The Distal Polybasic Cleavage Sites of SARS-CoV-2 Spike Protein Enhance Spike Protein-ACE2 Binding

Qiao

Cruz

2020

Preprint

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“…[ 14 ] Also, the arrangement of these interaction sites along polymer mainchains or side chains is also important to achieve higher steric matching with the complex surface structures of biomacromolecules. [ 15 ] If this is addressed in the near future, we believe these OEG‐based dendronized polymers would form a new kind of biomaterials for biomacromolecular recognition, and show promising applications for drug delivery, enzyme technology, and control of biological pathways in cells.…”

Section: Discussionmentioning

confidence: 99%

“…For example, random hetero‐copolymers were reported to provide confined microenvironments, which can preserve protein functions in foreign environment, [ 14 ] or exhibit selective proton transport across lipid bilayers at a rate similar to those of natural proton channels. [ 15 ] Recently, macromolecular crowding has been employed for material‐directed controlled self‐assembly, which improve performance of polymeric materials. [ 16 ] Generally speaking, confined microenvironment from synthetic polymers can be formed either through external stimuli‐induced changes of their physical properties [ 17,18 ] or through cooperative interactions of the polymers with topological structures such as in molecular polymer brushes [ 19 ] and dendronized polymers [ 20 ] ( Figure ).…”

Section: Introductionmentioning

confidence: 99%

Confined Microenvironments from Thermoresponsive Dendronized Polymers

Liu

et al. 2020

Macromol. Rapid Commun.

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Confined microenvironments in biomacromolecules arising from molecular crowding account for their well‐defined biofunctions and bioactivities. To mimick this, synthetic polymers to form confined structures or microenvironments are of key scientific value, which have received significant attention recently. To create synthetic confined microenvironments, molecular crowding effects and topological cooperative effects have been applied successfully, and the key is balance between self‐association of structural units and self‐repulsion from crowding‐induced steric hindrance. In this article, formation of confined microenvironments from stimuli‐responsive dendronized polymers carrying densely dendritic oligoethylene glycols (OEGs) moieties in their pendants is presented. These wormlike thick macromolecules exhibit characteristic thermoresponsive properties, which can provide constrained microenvironments to encapsulate effectively guest molecules including dyes, proteins, or nucleic acids to prevent their protonation or biodegradation. This efficient shielding effect can also mediate chemical reactions in aqueous phase, and even enhance chirality transferring efficiency. All of these can be switched off simply through the thermally‐induced dehydration and collapse of OEG dendrons due to the amphiphilicity of OEG chains. Furthermore, the switchable encapsulation and release of guests can be greatly enhanced when these dendronized polymers are used as major constituents for fabricating bulk hydrogels or nanogels, which provide a higher‐level confinement.

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“…These parameters were recommended for the accurate reproduction of the original CHARMM simulation on lipid membrane system 48 and were verified in simulations on proteins 24 , 49 , 50 and lipid membranes. 51 The production simulation lasted 100 ns. Calculation of the root-mean-square deviations of the RBD and ACE2 backbone atoms ( Figure S1 in the Supporting Information) supported that the structures of the RBD and ACE2 were both preserved except that mutant 1 displayed a relatively higher fluctuation.…”

Section: Methodsmentioning

confidence: 99%

Enhanced Binding of SARS-CoV-2 Spike Protein to Receptor by Distal Polybasic Cleavage Sites

2020

Self Cite

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The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein plays a crucial role in binding the human cell receptor ACE2 that is required for viral entry. Many studies have been conducted to target the structures of RBD–ACE2 binding and to design RBD-targeting vaccines and drugs. Nevertheless, mutations distal from the SARS-CoV-2 RBD also impact its transmissibility and antibody can target non-RBD regions, suggesting the incomplete role of the RBD region in the spike protein–ACE2 binding. Here, in order to elucidate distant binding mechanisms, we analyze complexes of ACE2 with the wild-type spike protein and with key mutants via large-scale all-atom explicit solvent molecular dynamics simulations. We find that though distributed approximately 10 nm away from the RBD, the SARS-CoV-2 polybasic cleavage sites enhance, via electrostatic interactions and hydration, the RBD–ACE2 binding affinity. A negatively charged tetrapeptide (GluGluLeuGlu) is then designed to neutralize the positively charged arginine on the polybasic cleavage sites. We find that the tetrapeptide GluGluLeuGlu binds to one of the three polybasic cleavage sites of the SARS-CoV-2 spike protein lessening by 34% the RBD–ACE2 binding strength. This significant binding energy reduction demonstrates the feasibility to neutralize RBD–ACE2 binding by targeting this specific polybasic cleavage site. Our work enhances understanding of the binding mechanism of SARS-CoV-2 to ACE2, which may aid the design of therapeutics for COVID-19 infection.

show abstract

Single-chain heteropolymers transport protons selectively and rapidly

Cited by 81 publications

References 48 publications

The Distal Polybasic Cleavage Sites of SARS-CoV-2 Spike Protein Enhance Spike Protein-ACE2 Binding

The Distal Polybasic Cleavage Sites of SARS-CoV-2 Spike Protein Enhance Spike Protein-ACE2 Binding

Confined Microenvironments from Thermoresponsive Dendronized Polymers

Enhanced Binding of SARS-CoV-2 Spike Protein to Receptor by Distal Polybasic Cleavage Sites

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